Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition.

This is the author accepted manuscript. The final version is available from American Association for the Advancement of Science via the DOI in this record.HSN2 is a nervous system-predominant exon of of the WNK1 kinase (HSN2-containing splice variant referred to as “WNK1/HSN2”) and is mutated in an autosomal recessive, inherited form of congenital pain insensitivity. We created a knockout mouse specifically lacking the HSN2 exon of WNK1. Although these mice had normal spinal neuron and peripheral sensory neuron morphology and distribution, the mice were less susceptible to hypersensitivity to cold and mechanical stimuli after peripheral nerve injury. In contrast, thermal and mechanical nociceptive responses were similar to control mice in an inflammation-induced pain model. In the nerve injury model of neuropathic pain, WNK1/HSN2 contributed to a maladaptive decrease in the activity of the K+-Clcotransporter KCC2 by increasing its inhibitory phosphorylation at Thr906 and Thr1007, resulting in an associated loss of GABA-mediated inhibition of spinal paintransmitting nerves. Electrophysiological analysis showed that WNK1/HSN2 shifted the concentration of Clsuch that GABA signaling resulted in depolarization (increased neuronal activity) rather than hyperpolarization (decreased neuronal activity) in mouse spinal nerves. Consistent with the results in the WNK1/HSN2-deficient mice, pharmacologically antagonizing WNK1/HSN2 normalized pathological GABA depolarization of injured spinal cord lamina II neurons. These data provide mechanistic insight into, and a compelling therapeutic target for, neuropathic pain after nerve injury.This work was supported by the Canadian Institutes of Health Research [grant number 179251] to GAR; the Manton Center for Orphan Disease Research at Boston Children’s Hospital and Harvard Medical School, and a Harvard-MIT Basic Neuroscience Grant to KTK; the Réseau de Médecine Génétique appliquée, Claude Laberge postdoctoral fellowship to VL; the Fonds de la Recherche en Santé du Québec postdoctoral fellowship to VL; the Canadian Institutes of Health Research postodoctoral fellowship to JFS; and RO1DE022912 grant to AL